1,6 Naphthridines useful as inhibitors of SYK kinase

ABSTRACT

Disclosed are compounds of formula (I): 
                         
wherein R 3 , R 5 , R 7  and R 8  are defined herein, which are useful as inhibitors SYK kinase and are thus useful for treating diseases resulting from inappropriate mast cell activation, which include allergic and inflammatory diseases. Also disclosed are pharmaceutical compositions comprising these compounds and processes for preparing these compounds.

Related Applications

The present application is a division of U.S. patent application No.12/014,190 filed Jan. 15, 2008, now allowed, which is a continuation ofU.S. patent application Ser. No. 10/413,980, filed April, 15, 2003, nowU.S. Pat. No. 7,321,041, which is a continuation U.S. patent applicationSer. No. 10/029,714, filed Dec. 21, 2001, (now abandoned), the contentsof each of which is hereby incorporated by reference in their entirety.

TECHNICAL FIELD OF THE INVENTION

This invention relates to substituted [1,6]-naphthyridines that inhibitSYK kinase. In one embodiment, this invention relates to a novel classof substituted [1,6]-naphthyridines and pharmaceutical compositionscomprising these compounds. This invention also relates to methods forproducing such novel [1,6]-naphthyridines. Because of the ability ofthese compounds to inhibit SYK kinase, the compounds and pharmaceuticalcompositions of this invention are particularly well suited forpreventing and treating inflammatory and allergic diseases.

BACKGROUND OF THE INVENTION

Mast cells play a critical role in asthma and allergic disorders byreleasing pro-inflammatory mediators and cytokines. Antigen-mediatedaggregation of FcεRI, the high-affinity receptor for IgE results inactivation of mast cells. This triggers a series of signaling eventsresulting in the release of mediators, including histamine, proteases,leukotrienes and cytokines. These mediators cause increased vascularpermeability, mucus production, bronchoconstriction, tissue degradationand inflammation, thus playing key roles in the etiology and symptoms ofasthma and allergic disorders.

One of the key events in the signaling pathway following the activationof mast cells is activation of the tyrosine kinase SYK. SYK kinase actsas a central initiator of all subsequent signaling leading to mediatorrelease. The critical role of SYK kinase in the signaling path wasdemonstrated by the complete inhibition of mediator release by a proteincontaining the SH2 domains of SYK kinase that functioned as an inhibitorof SYK kinase (J. A. Taylor et al., Molec. and Cell Biol., 1995, 15,4149). Furthermore, direct clustering of SYK, introduced into a mastcell line as part of a chimeric transmembrane protein, was found to besufficient to stimulate the events leading to mediator release normallyinduced by clustering of FcεRI (V. M. Rivera and J. S. Brugge, Molec.and Cell. Biol., 1995, 15, 1582).

ER-27319 (3,4-dimethyl-10-(3-aminopropyl)-9-acridone oxalate), acompound reported to interfere with the activation of SYK, has beenshown to inhibit anti-IgE mediated degranulation in rodent and humanmast cells (K. Moriya et al., Proc. Nat. Acad. Sci. USA, 1997, 94,12539). Concentrations of piceatannol(3,4,3′5′-tetrahydroxy-trans-stilbene), a non-selective SYK kinaseinhibitor, that inhibited the antigen-stimulated phosphorlation of SYKalso inhibited functional responses in mast cells, including mediatorrelease (J. M. Oliver et. al., J. Biol. Chem., 1994, 269, 29697).

The conclusion from the studies described above is that SYK kinaseactivation and activity is required for FcεRI-mediated release ofmediators from mast cells. Therefore, agents that block the activity ofSYK kinase act to block the release of allergic and pro-inflammatorymediators and cytokines. These agents have potential utility in treatinginflammatory and allergic disorders including asthma, chronicobstructive pulmonary disease (COPD), adult respiratory distresssyndrome (ARDS), ulcerative colitis, Crohn's disease, bronchitis,conjunctivitis, psoriasis, scleroderma, urticaria, dermatitis andallergic rhinitis.

In addition to the inhibitors mentioned above, WO 0109134 disclosespurine derivatives as inhibitors of SYK kinase. WO 9931073 describespyrimidine -5-carboxamide derivatives as inhibitors of SYK kinase. WO0147922 describes substituted azaindoles useful in the treatment ofdisease states capable of being modulated by the inhibition of proteinkinases, in particular SYK kinase. WO 9818782 describes inhibitors ofZAP70 that are also reported to inhibit SYK.

In addition to mast cells, SYK is expressed in other hematopoietic cellsincluding B cells, where it is thought to play an essential role intransducing signals required for the transition of immature B cells intomature recirculating B cells (M. Turner et al., Immunology Today, 2000,21, 148). B cells are reported to play an important role in someinflammatory conditions such as lupus (O. T. Chan et al., ImmunologicalRev., 1999, 169, 107) and rheumatoid arthritis (A. Gause and C. Borek,Biodrugs, 2001, 15, 73).

SYK was also reported to be an element of the signaling cascade inbeta-amyloid and prion fibrils leading to production of neurotoxicproducts (C. K. Combs et al., J. Neurosci., 1999, 19, 928). Furthermore,an inhibitor of SYK blocked the production of these neurotoxic products.Thus a SYK inhibitor would potentially be useful in the treatment ofAlzheimer's disease and related neuroinflammatory diseases. Anotherreport (Y. Kuno et al., Blood, 2001, 97, 1050) demonstrates that SYKplays an important role in malignant progression. A TEL-SYK fusionprotein was found to transform hematopoietic cells suggesting a role inthe pathogenesis of hematopoietic malignancies. Therefore a SYKinhibitor may be useful in the treatment of certain types of cancers.

A recent report suggests that SYK is a mediator of epithelial cellgrowth and suggests that it could be a potential tumor-suppressor inhuman breast carcinomas (P. J. P. Coopman et al., Nature, 2000, 406,742). One could conclude from this report that while inhibition of SYKkinase activity could be desirable for treatment of inflammatory andallergic disease and asthma, a complete, irreversible blockade of SYKkinase activity may not be desirable.

BE 835,770 describes 5-amino-1,6-naphthyridines having antimicrobialactivity. U.S. Pat. No. 3,928,367, U.S. Pat. No. 4,017,500, U.S. Pat.No. 4,115,395 and U.S. Pat. No. 4,260,759 describe5-amino-1,6-naphthyridines having antifungal and antibacterial activity.WO 9918077 describes 5-piperazinyl-1,6-naphthyridines as serotoninantagonists.

BRIEF DESCRIPTION OF THE INVENTION

The work cited above supports the principle that inhibition of SYKkinase will be beneficial in the treatment of various disease states. Itis therefore an object of the invention to provide novel compounds whichinhibit SYK kinase

It is a further object of the invention to provide methods for treatingdiseases and pathological conditions mediated by SYK kinase such asinflammatory and allergic disorders including asthma, chronicobstructive pulmonary disease (COPD), adult respiratory distresssyndrome (ARDS), ulcerative colitis, Crohn's disease, bronchitis,conjunctivitis, psoriasis, scleroderma, urticaria, dermatitis allergicrhinitis, lupus and rheumatoid arthritis using the novel compounds ofthe invention.

It is yet a further object of the invention to provide processes ofpreparation for the above-mentioned novel compounds and pharmaceuticalcompositions comprising the same.

DETAILED DESCRIPTION OF THE INVENTION

In its broadest generic aspect, the invention provides novel compoundsof the formula (I) below:

wherein:

-   R₃ is H, C₁₋₃alkyl, halogen or phenyl;-   R₅ is N(R₉)(R₁₀) or OR₁₁ wherein    -   R₉ is H or C₁₋₃alkyl,    -   R₁₀ is aminoC₂₋₆alkyl, C₁₋₄alkylaminoC₂₋₆alkyl,        diC₁₋₄alkylaminoC₂₋₆alkyl, C₁₋₄alkoxyC₂₋₆alkyl or        hydroxyC₂₋₆alkyl, wherein one methylene group in said C₂₋₆alkyl        is optionally replaced with an oxygen, sulfur, NH, or NCH₃, and        wherein each methylene group in said C₂₋₆alkyl is optionally        substituted with a halogen, cyano or hydroxy group, or R₁₀ is        C₃₋₇cycloalkyl, heterocycloalkyl, heteroaryl,        C₃₋₇cycloalkylC₁₋₄alkyl, heterocycloalkylC₁₋₄alkyl,        arylC₁₋₄alkyl or heteroarylC₁₋₄alkyl each optionally substituted        with one or more C₁₋₄alkyl, amino, C₁₋₄alkylamino,        diC₁₋₄alkylamino, aminoC₁₋₃alkyl, C₁₋₄alkylaminoC₁₋₃alkyl,        diC₁₋₄alkylaminoC₁₋₃alkyl, halogen, hydroxy, aminocarboxy or        benzyl groups, or R₉ and R₁₀ together with the nitrogen they are        bonded to may form a heterocycloalkyl group containing one or        more heteroatoms which is optionally substituted with one or        more C₁₋₄alkyl, amino, C₁₋₄alkylamino, diC₁₋₄alkylamino,        aminoC₁₋₃alkyl, C₁₋₄alkylaminoC₁₋₃alkyl,        diC₁₋₄alkylaminoC₁₋₃alkyl, halogen, hydroxy, aminocarboxy or        benzyl groups, and    -   R₁₁ is aminoC₂₋₆alkyl, C₁₋₄alkylaminoC₂₋₆alkyl,        diC₁₋₄alkylaminoC₂₋₆alkyl, C₁₋₄alkoxyC₂₋₆alkyl or        hydroxyC₂₋₆alkyl, wherein one methylene group in said C₂₋₆alkyl        is optionally replaced with an oxygen, sulfur, NH, or NCH₃, and        wherein each methylene group in said C₂₋₆alkyl is optionally        substituted with a halogen, cyano or hydroxy group, or R₁₁ is        C₃₋₇cycloalkyl, heterocycloalkyl, heteroaryl,        C₃₋₇cycloalkylC₁₋₄alkyl, heterocycloalkylC₁₋₄alkyl,        arylC₁₋₄alkyl or heteroarylC₁₋₄alkyl each optionally substituted        with one or more C₁₋₄alkyl, amino, C₁₋₄alkylamino,        diC₁₋₄alkylamino, aminoC₁₋₃alkyl, C₁₋₄alkylaminoC₁₋₃alkyl,        diC₁₋₄alkylaminoC₁₋₃alkyl, halogen, hydroxy, aminocarboxy or        benzyl groups;-   R₇ is phenyl, naphthyl, furyl, thienyl, pyridyl, indolyl,    benzothiazolyl or pyrrolyl optionally substituted with one or more    C₁₋₃alkoxy, halogen, CF₃, CF₃O, hydroxy, C₁₋₃alkyl, amino,    C₁₋₃alkylamino, diC₁₋₃alkylamino, C₁₋₃alkylaminoC₁₋₃alkyl,    diC₁₋₃alkylaminoC₁₋₃alkyl,    (C₁₋₃alkylaminoC₁₋₃alkyl)(C₀₋₃alkyl)amino,    (diC₁₋₃alkylaminoC₁₋₃alkyl)(C₀₋₃alkyl)amino, C₁₋₃alkylthio,    aminocarboxy, C₁₋₃alkylcarbonyl, ureido optionally substituted with    C₁₋₃alkyl, C(O)OC ₁₋₄alkyl, C(O)OH , acetamido or heterocycloaklyl    groups, or with a phenyl group which is optionally substituted with    one or more C₁₋₃alkoxy, halogen, CF₃, CF₃O, hydroxy, C₁₋₃alkyl,    amino, C₁₋₃alkylamino, diC₁₋₃alkylamino, C₁₋₃alkylaminoC₁₋₃alkyl,    diC₁₋₃alkylaminoC₁₋₃alkyl, C₁₋₃alkylthio, aminocarboxy,    C₁₋₃alkylcarbonyl, ureido optionally substituted with C₁₋₃alkyl,    C(O)OC₁₋₄alkyl, C(O)OH, acetamido, heteroaryl or heterocycloalkyl    groups; and-   R₈ is H, halogen or cyano.

In another embodiment of the invention, there are provided compounds ofthe formula (I) as described immediately above, and wherein:

-   R₃ is H or methyl;-   R₅ is N(R₉)(R₁₀) or OR₁₁ wherein    -   R₉ is H or methyl,    -   R₁₀ is aminoC₂₋₆alkyl, C₁₋₄alkylaminoC₂₋₆alkyl,        diC₁₋₄alkylaminoC₂₋₆alkyl, C₁₋₄alkoxyC₂₋₆alkyl or        hydroxyC₂₋₆alkyl, wherein one methylene group in said C₂₋₆alkyl        is optionally replaced with an oxygen, sulfur, NH, or NCH₃, and        wherein each methylene group in said C₂₋₆alkyl is optionally        substituted with a halogen, cyano or hydroxy group, or R₁₀ is        C₄₋₇cycloalkyl, heterocycloalkyl selected from pyrrolidinyl and        piperidinyl, heteroaryl selected from oxazolyl, isoxazolyl,        pyridyl and pyrimidinyl, C₃₋₆cycloalkylC₁₋₄alkyl,        heterocycloalkylC₁₋₄alkyl wherein said heterocycloalkyl is        selected from morpholinyl, pyrrolidinyl, pyrrolidin-2-onyl,        piperidinyl, tetrahydrofuranyl and piperazinyl, phenylC₁₋₄alkyl        or heteroarylC₁₋₄alkyl wherein said heteroaryl is selected from        pyridyl, furyl, and imidazolyl, each optionally substituted with        one or more C₁₋₄alkyl, amino, C₁₋₄alkylamino, diC₁₋₄alkylamino,        aminoC₁₋₃alkyl, C₁₋₄alkylaminoC₁₋₃alkyl,        diC₁₋₄alkylaminoC₁₋₃alkyl, halogen, hydroxy, aminocarboxy or        benzyl groups, or R₉ and R₁₀ together with the nitrogen they are        bonded to may form a heterocycloalkyl group selected from        piperidinyl, piperazinyl, pyrrolidinyl and morpholinyl which is        optionally substituted with one or more C₁₋₄alkyl, amino,        C₁₋₄alkylamino, diC₁₋₄alkylamino, aminoC₁₋₃alkyl,        C₁₋₄alkylaminoC₁₋₃alkyl, diC₁₋₄alkylaminoC₁₋₃alkyl, halogen,        hydroxy, aminocarboxy or benzyl groups, and    -   R₁₁ is is aminoC₂₋₆alkyl, C₁₋₄alkylaminoC₂₋₆alkyl,        diC₁₋₄alkylaminoC₂₋₆alkyl, C₁₋₄alkoxyC₂₋₆alkyl or        hydroxyC₂₋₆alkyl, wherein one methylene group in said C₂₋₆alkyl        is optionally replaced with an oxygen, sulfur, NH, or NCH₃, and        wherein each methylene group in said C₂₋₆alkyl is optionally        substituted with a halogen, cyano or hydroxy group, or R₁₁ is        C₅₋₇cyclohexyl, heterocycloalkyl selected from pyrrolidinyl and        piperidinyl, heteroaryl selected from oxazolyl, isoxazolyl,        pyridyl and pyrimidinyl, C₃₋₆cycloalkylC₁₋₄alkyl,        heterocycloalkylC₁₋₄alkyl wherein said heterocycloalkyl is        selected from morpholinyl, pyrrolidinyl, pyrrolidin-2-onyl,        piperidinyl, tetrahydrofuranyl and piperazinyl, phenylC₁₋₄alkyl        or heteroarylC₁₋₄alkyl wherein said heteroaryl is selected from        pyridyl, furyl, and imidazolyl, each optionally substituted with        one or more C₁₋₄alkyl, amino, C₁₋₄alkylamino, diC₁₋₄alkylamino,        aminoC₁₋₃alkyl, C₁₋₄alkylaminoC₁₋₃alkyl,        diC₁₋₄alkylaminoC₁₋₃alkyl, halogen, hydroxy, aminocarboxy or        benzyl groups;-   R₇ is phenyl, naphthyl, furyl, thienyl, pyridyl, indolyl,    benzothiazolyl or pyrrolyl optionally substituted with one or more    C₁₋₃alkoxy, halogen, CF₃, CF₃O, hydroxy, C₁₋₃alkyl, amino,    C₁₋₃alkylamino, diC₁₋₃alkylamino, C₁₋₃alkylaminoC₁₋₃alkyl,    diC₁₋₃alkylaminoC₁₋₃alkyl,    (C₁₋₃alkylaminoC₁₋₃alkyl)(C₀₋₃alkyl)amino,    (diC₁₋₃alkylaminoC₁₋₃alkyl)(C₀₋₃alkyl)amino, C₁₋₃alkylthio,    aminocarboxy, ureido optionally substituted with C₁₋₃alkyl,    acetamido or heterocycloalkyl groups, or with a phenyl group which    is optionally substituted with one or more C₁₋₃alkoxy, halogen, CF₃,    CF₃O, hydroxy, C₁₋₃alkyl, amino, C₁₋₃alkylamino, diC₁₋₃alkylamino,    C₁₋₃alkylaminoC₁₋₃alkyl, diC₁₋₃alkylaminoC₁₋₃alkyl, C₁₋₃alkylthio,    aminocarboxy, C₁₋₃alkylcarbonyl, ureido optionally substituted with    C₁₋₃alkyl, C(O)OC₁₋₄alkyl, C(O)OH, acetamido, heteroaryl or    heterocycloalkyl groups; and-   R₈ is H.

In another embodiment of the invention there are provided compounds ofthe formula (I) as described immediately above, and wherein:

-   R₅ is N(R₉)(R₁₀) or OR₁₁ wherein    -   R₉ is H or methyl,    -   R₁₀ is aminoC₂₋₆alkyl, methylaminoC₂₋₆alkyl,        dimethylaminoC₂₋₆alkyl, methoxyC₂₋₆alkyl or hydroxyC₂₋₆alkyl,        wherein one methylene group in said C₂₋₆alkyl is optionally        replaced with an oxygen or sulfur, and wherein each methylene        group in said C₂₋₆alkyl is optionally substituted with a hydroxy        group, or R₁₀ is C₄₋₇cycloalkyl, heterocycloalkyl selected from        pyrrolidinyl and piperidinyl, heteroaryl selected from oxazolyl,        isoxazolyl, pyridyl and pyrimidinyl, C₃₋₆cycloalkylC₁₋₄alkyl,        heterocycloalkylC₁₋₄alkyl wherein said heterocycloalkyl is        selected from, pyrrolidin-2-only and piperidinyl, benzyl or        heteroarylC₁₋₄alkyl wherein said heteroaryl is selected from        pyridyl and imidazolyl, each optionally substituted with one or        more amino, aminomethyl, methylaminomethyl, dimethylaminomethyl,        hydroxy, aminocarboxy or benzyl groups, or R₉ and R₁₀ together        with the nitrogen they are bonded to may form a heterocycloalkyl        group selected from piperidinyl, piperazinyl, pyrrolidinyl and        morpholinyl which is optionally substituted with one or more        amino, hydroxy or aminocarboxy groups, and    -   R₁₁ is aminoC₂₋₆alkyl, methylaminoC₂₋₆alkyl,        dimethylaminoC₂₋₆alkyl, methoxyC₂₋₆alkyl or hydroxyC₂₋₆alkyl,        wherein one methylene group in said C₂₋₆alkyl is optionally        replaced with an oxygen or sulfur, and wherein each methylene        group in said C₂₋₆alkyl is optionally substituted with a hydroxy        group, or R₁₁ is C₅₋₇cycloalkyl, heterocycloalkyl selected from        pyrrolidinyl and piperidinyl, heteroaryl selected from oxazolyl,        isoxazolyl, pyridyl and pyrimidinyl, C₃₋₆cycloalkylC₁₋₄alkyl,        heterocycloalkylC₁₋₄alkyl wherein said heterocycloalkyl is        selected from, pyrrolidin-2-only and piperidinyl, benzyl or        heteroarylC₁₋₄alkyl wherein said heteroaryl is selected from        pyridyl and imidazolyl, each optionally substituted with one or        more amino, aminomethyl, hydroxy, aminocarboxy, benzyl,        methylaminomethyl, or dimethylaminomethyl groups;-   R₇ is phenyl, optionally substituted in the 3-, 4- or 5-positions    with one or more methoxy, fluorine, chlorine, bromine, CF₃, CF₃O,    C₁₋₃alkyl, diC₁₋₃alkylamino, diC₁₋₃alkylaminoC₁₋₃alkyl,    (C₁₋₃alkylaminoC₁₋₃alkyl)(C₀₋₃alkyl)amino,    (diC₁₋₃alkylaminoC₁₋₃alkyl)(C₀₋₃alkyl)amino, thiomethoxy, acetamido,    4-morpholinyl, 1-piperidinyl or 1-pyrrolidinyl groups, or    substituted in the 4-position with a phenyl group optionally    substituted in the 4-position with a methyl, methoxy, 2-thienyl or    3-pyridyl group, or R₇ is a 2-naphthyl or 2-thienyl group or a    5-indoyl group optionally substituted in the 1-position with a CF₃,    C₁₋₃alkyl, diC₁₋₃alkylaminoC₁₋₃alkyl, or C₁₋₃alkylaminoC₁₋₃alkyl    group; and-   R₈ is H.

In yet another embodiment of the invention there are provided compoundsof the formula (I) as described immediately above, and wherein:

-   R₃ is H;-   R₅ is N(R₉)(R₁₀) or OR₁₁ wherein    -   R₉ is H or methyl,    -   R₁₀ is aminoC₃₋₄alkyl or hydroxyC₃₋₄alkyl wherein each methylene        group in said C₃₋₄alkyl is optionally substituted with a hydroxy        group, or R₁₀is C₅₋₇cycloalkyl substituted with an amino or        hydroxy group, and    -   R₁₁ is aminoC₃₋₄alkyl or hydroxyC₃₋₄alkyl wherein each methylene        group in said C₃₋₄alkyl is optionally substituted with a hydroxy        group, or R₁₁ is C₅₋₇cycloalkyl substituted with an amino or        hydroxy group;-   R₇ is phenyl, substituted in the 4-position with a diC₁₋₂alkylamino,    (dimethylaminoC₂₋₃alkyl)(C₀₋₃alkyl)amino, isopropyl, 4-morpholinyl,    4-piperidinyl or 4-pyrrolidinyl group and optionally substituted in    the 3-position with a chlorine, bromine or methoxy group; and-   R₈ is H.

In a further embodiment of the invention, there are provided thefollowing compounds:

In another embodiment of the invention, there are provided the followingcompounds:

The invention includes pharmaceutically acceptable derivatives ofcompounds of formula (I). A “pharmaceutically acceptable derivative”refers to any pharmaceutically acceptable acid, salt or ester of acompound of this invention, or any other compound which, uponadministration to a patient, is capable of providing (directly orindirectly) a compound of this invention, a pharmacologically activemetabolite or pharmacologically active residue thereof.

Pharmaceutically acceptable salts of the compounds of this inventioninclude those derived from pharmaceutically acceptable inorganic andorganic acids and bases. Examples of suitable acids includehydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric,maleic, phosphoric, glycolic, lactic, salicylic, succinic,toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic, formic,benzoic, malonic, naphthalene-2-sulfonic and benzenesulfonic acids.Other acids, such as oxalic acid, while not themselves pharmaceuticallyacceptable, may be employed in the preparation of salts useful asintermediates in obtaining the compounds of this invention and theirpharmaceutically acceptable acid addition salts. Salts derived fromappropriate bases include alkali metal (e.g., sodium), alkaline earthmetal (e.g., magnesium), ammonium and N-(C₁-C₄ alkyl)₄ ⁺ salts.

In addition, the compounds of this invention include prodrugs ofcompounds of the formula (I). Prodrugs include those compounds that,upon simple transformation, are modified to produce the compounds of theinvention. Simple chemical transformations include hydrolysis, oxidationand reduction which occur enzymatically, metabolically or otherwise.Specifically, when a prodrug of this invention is administered to apatient, the prodrug may be transformed into a compound of formula (I),thereby imparting the desired pharmacological effect.

Any compounds of this invention containing one or more asymmetric carbonatoms may occur as racemates and racemic mixtures, single enantiomers,diastereomeric mixtures and individual diastereomers. All such isomericforms of these compounds are expressly included in the presentinvention. Each stereogenic carbon may be in the R or S configuration,or a combination of configurations.

Some of the compounds of the invention can exist in more than onetautomeric form. The invention includes all such tautomers.

The compounds of the invention are only those which are contemplated tobe ‘chemically stable’ as will be appreciated by those skilled in theart. For example, a compound which would have a ‘dangling valency’, or a‘carbanion’ are not compounds contemplated by the invention.

As used herein, the following abbreviations are used:

-   BuOH is butanol;-   DMF is dimethylformamide;-   DMSO is dimethyl sulfoxide-   EtOAc is ethyl acetate;-   EtOH is ethanol;-   HPLC is high-performance liquid chromatography-   LDA is lithium diisopropylamide;-   MeOH is methanol;-   THF is tetrahydrofuran;-   TLC is thin layer chromatography

All terms as used herein in this specification, unless otherwise stated,shall be understood in their ordinary meaning as known in the art. Forexample, “C₁₋₆alkoxy” is a C₁₋₆alkyl with a terminal oxygen, such asmethoxy, ethoxy, propoxy, pentoxy and hexoxy. All alkyl, alkylene oralkynyl groups shall be understood as being branched or unbranchedunless otherwise specified. Other more specific definitions are asfollows:

The term “alkyl” refers to a saturated aliphatic radical containing fromone to ten carbon atoms or a mono- or polyunsaturated aliphatichydrocarbon radical containing from two to twelve carbon atoms unlessotherwise stated. The mono- or polyunsaturated aliphatic hydrocarbonradical contains at least one double or triple bond, respectively.“Alkyl” refers to both branched and unbranched alkyl groups. Examples of“alkyl” include alkyl groups which are straight chain alkyl groupscontaining from one to eight carbon atoms and branched alkyl groupscontaining from three to ten carbon atoms. Other examples include loweralkyl groups which are straight chain alkyl groups containing from oneto six carbon atoms and branched alkyl groups containing from three tosix carbon atoms. It should be understood that any combination termusing an “alk” or “alkyl” prefix refers to analogs according to theabove definition of “alkyl”. For example, terms such as “alkoxy”,“alkythio” refer to alkyl groups linked to a second group via an oxygenor sulfur atom. “Alkanoyl” refers to an alkyl group linked to a carbonylgroup (C═O). Each alkyl or alkyl analog described herein shall beunderstood to be optionally partially or fully halogenated.

The term “cycloalkyl” refers to the cyclic analog of an alkyl group, asdefined above. Examples of cycloalkyl groups are saturated orunsaturated nonaromatic cycloalkyl groups containing from three to eightcarbon atoms, and other examples include cycloalkyl groups having threeto six carbon atoms.

The term “heterocycloalkyl” refers to a stable 4-8 membered (butpreferably, 5 or 6 membered) monocyclic or 8-11 membered bicyclicheterocycle radical which may be either saturated or unsaturated, and isnon-aromatic. Each heterocycle consists of carbon atoms and from 1 to 4heteroatoms chosen from nitrogen, oxygen and sulfur. The heterocycle maybe attached by any atom of the cycle, which results in the creation of astable structure. Examples of “heterocycloalkyl” include radicals suchas pyrrolinyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, piperidinyl,morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, azetidinyl,tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrofuranyl,hexahydropyrimidinyl, hexahydropyridazinyl, dihydro-oxazolyl,1,2-thiazinanyl-1,1-dioxide, 1,2,6-thiadiazinanyl-1,1-dioxide,isothiazolidinyl-1,1-dioxide and imidazolidinyl-2,4-dione.

The term “halogen” refers to bromine, chlorine, fluorine or iodine.

The term “aryl” shall be understood to mean a 6-12 membered aromaticcarbocycle, which can be a single ring or can be multiple rings fusedtogether or linked covalently. The term “aryl” includes, for example,phenyl and naphthyl; other terms comprising “aryl” will have the samedefinition for the aryl component, examples of these moieties include:arylalkyl, aryloxy or arylthio.

The term “heteroaryl” refers to a stable 5-8 membered (but preferably, 5or 6 membered) monocyclic or 8-11 membered bicyclic aromatic heterocycleradical. Each heterocycle consists of carbon atoms and from 1 to 4heteroatoms chosen from nitrogen, oxygen and sulfur. The heteroarylgroup may be attached by any atom of the ring which results in thecreation of a stable structure. Examples of “heteroaryl” includeradicals such as furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl,tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, indolizinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl,indazolyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, purinyl,quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl,quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl,acridinyl, phenazinyl, phenothiazinyl and phenoxazinyl,

As used herein above and throughout this application, “nitrogen” and“sulfur” include any oxidized form of nitrogen and sulfur and thequaternized form of any basic nitrogen.

General Synthetic Methods

The invention additionally provides for methods for making the compoundsof the formula (I). The compounds of the invention may be prepared bythe general methods and examples presented below, and methods known tothose of ordinary skill in the art.

Reaction progress may be monitored by conventional methods such as thinlayer chromatography (TLC). Intermediates and products may be purifiedby methods known in the art, including column chromatography, HPLC orrecrystallization.

As illustrated in Scheme I, a 2-methylnicotinic acid derivative (II) istreated with a strong base such as lithium diisopropylamide (LDA) in asuitable solvent such as THF at about −78° C. to 0° C. to form thedianion. This is followed by addition of a nitrile bearing the desiredR₇, preferably at about −78° C., and allowing the reaction to warm toabout room temperature until reaction is complete to provide the[1,6]-naphthyridin-5-ol (III), which may also exist as the tautomeric6H-[1,6]-naphthyridin-5-one (IIIa).

The [1,6]-naphthyridin-5-ol is then treated with a suitable halogenatingagent. For example, treatment with POCl₃, optionally in the presence ofa suitable base such as N,N-diethylaniline, at a temperature of about 0°C. to 140° C., preferably at about 100° C. to 135° C., provides the5-chloro-[1,6]-naphthyridine IV. This may then be reacted with an excessof the desired amine (R′NH₂) at a suitable temperature, preferably about100° C. to 140° C., optionally in a sealed reaction vessel, to provide acompound of formula (I) having an amine at R₅. If a compound of formula(I) having an ether link at R₅ is desired, one may react IV with thedesired alcohol (R′OH), in the presence of a suitable base such assodium hydride in a suitable solvent such as DMF at a temperature ofabout 0° C. to 100° C., preferably at about room temperature.

If a compound of formula (I) having R₈ being a substituent other thanhydrogen is desired, one may react an intermediate of formula (III) witha halogenating agent, preferably N-iodosuccinamide, in a suitablesolvent such as DMF, at about room temperature, to provide the 8-iodointermediate V (Scheme II). The 8-iodo substituent may then be convertedto other desired R₈ by methods known to those skilled in the art.Likewise, R₅ or R₇ may be reacted further by methods known to thoseskilled in the art to prepare additional compounds of formula (I).Several illustrative examples are provided in the Experimental section.

The [1,6]-naphthyridin-5-ol III may also be prepared by an alternativeprocedure illustrated in Scheme III (Method E).

In this procedure, described in the literature (D. E. Ames and W. D.Dodds, J. C. S. Perkin I, 1972, 705), a carbanion is reacted with a2-halonicotinic acid, preferably a 2-chloro- or 2-bromonicotinic acid,(VI), in the presence of a copper catalyst, preferably copper acetate,to give a 2-(2-substituted-2-oxo-ethyl)nicotinic acid intermediate(VIII). The carbanion may be generated from a 1,3-dicarbonyl compoundsuch as VII, and a base, preferably sodium ethoxide. Subsequentethanolysis cleaves the acetyl group to provide VIII. Treatment of VIIIwith ammonia in a suitable solvent, such as dioxane or ethanol, at asuitable temperature, preferably the reflux temperature of the solvent,provides III.

In a variation of Method E illustrated in Scheme IV (Method F),intermediate VIII may be treated with aqueous acid, such as aqueoussulfuric acid, at about room temperature to provide apyrano[4,3-b]pyridin-5-one (IX). This may then be treated with ammoniain a suitable solvent such as ethanol, at a suitable temperature,preferably about the reflux temperature, to provide III.

SYNTHETIC EXAMPLES

The following examples are for the purpose of illustrating preferredembodiments of this invention, and are not to be construed as limitingthe scope of the invention in any way.

7-Aryl-5-amino-[1,6]naphthyridines may be made by the proceduredescribed in Examples 1-3 below (Methods A-C). By choosing theappropriately substituted aryl nitrile (Example 1) and appropriatelysubstituted amine (Example 3) or alcohol (Example 11) one may obtain thedesired compound of formula (I). Alternatively, one may obtain aprecursor of the desired compound, which may be further modifiedsynthetically by methods known to those skilled in the art to obtain thedesired compound of formula (I).

Example 1 7-(4-Dimethylaminophenyl)-[1,6]naphthyridin-5-ol (Method A)

To a suspension of 2-methylnicotinic acid (1.37 g, 10 mmol) in THF (20mL), lithium diisopropylamide (2 M solution in THF, 12.5 mL, 25 mmol)was added dropwise at −78° C. The resulting mixture was stirred at −78°C. for 30 minutes then slowly warmed up to 0° C. over 1.5 hours. Themixture was cooled to −78 ° C. and a solution of4-dimethylaminophenylnitrile (2.19 g, 15 mmol) in THF (10 mL) was addeddropwise. The mixture was slowly warmed to room temperature and stirredfor 16 hours. Water (20 mL) was added and the THF was removed in vacuo.EtOAc (10 mL) was added and the solution was allowed to stand for twohours. The precipitated solid was collected by filtration to afford thetitle compound as a yellow solid (1.2 g). ¹H NMR (CDCl₃, 400 MHz) δ11.58 (b, 1H), 8.86 (dd, 1H), 8.45 (d, 1H), 6.86 (d, 1H), 3.92 (s, 3H),3.88 (s, 3H), 2.87 (s, 6H), MS (m/e) calculated for C₁₅H₁₅N₃O 265, found266.2 (M+H).

Example 2 5-Chloro-7-(4-dimethylaminophenyl)-[1,6]naphthyridine (MethodB)

A mixture of 7-(4-dimethylaminophenyl)-[1,6]naphthyridin-5-ol(Example 1) (1.2 g, 5 mmol), POCl₃ (10 mL) and N,N-diethylaniline (0.15g, 1.0 mmol) were stirred at 110° C. for 16 hours. The contents werecooled to room temperature and excess POCl₃ was removed in vacuo. Theresidue was quenched with water and neutralized with aqueous sodiumcarbonate. The aqueous solution was then extracted with dichloromethane(2×30 mL). The combined organic extracts were dried over anhydrousmagnesium sulfate and concentrated in vacuo to give a tan oil.Purification by flash chromatography eluting with hexanes/EtOAc (1:1)afforded the title compound as a yellowish solid (1.1 g). ¹H NMR (CDCl₃,400 MHz) δ 9.03 (dd, 1H), 8.54 (d, 1H), 8.13 (s, 1H), 8.08 (d, 2H), 7.46(dd, 1H), 6.81 (d, 2H), 3.05 (s, 6H).

Example 35-(3-Aminopropylamino)-7-(4-dimethylaminophenyl)-[1,6]naphthyridine(Method C)

A mixture of 5-chloro-7-(4-dimethylaminophenyl)-[1,6]naphthyridine(Example 2) (10 mg, 0.035 mmol) and 1,3-diaminopropane (200 microL, 2.4mmol) was stirred at 100 ° C. for 5 hours. After cooling to roomtemperature, water was added and the resulting mixture was extractedwith dichloromethane (2×3 mL). Purification by preparative thin layerchromatography afforded the title compound as a yellow film (8.5 mg). ¹HNMR (CDCl₃, 400 MHz) δ 8.85 (dd, 1H), 8.10 (d, 2H), 8.07 (d, 1H), 7.50(s, 1H), 7.21 (dd, 1H), 6.81 (d, 2H), 3.87 (t, 2H), 3.02 (s, 6H), 2.97(t, 2H), 1.90 (quint, 2H); MS (m/e) calculated for C₁₉H₂₃N₅ 321.2, found322.4 (M+H).

Examples 4-13 are illustrative of procedures that may be used to modifyintermediates to obtain desired compounds of the invention.

Example 4 5-Chloro-7-(3-hydroxyphenyl)-[1,6]naphthyridine

To a solution of 5-chloro-7-(3-methoxyphenyl)-[1,6]naphthyridine (0.052g, 0.2 mmol) in dichloromethane (2 mL) was added boron tribromide (1 Msolution in dichloromethane, 0.4 mL, 0.4 mmol) at −78° C. The resultingmixture was slowly warmed to room temperature. The residue was quenchedwith water and neutralized with aqueous sodium carbonate. The aqueoussolution was then extracted with dichloromethane (2×30 mL). The combinedorganic extracts were dried over anhydrous magnesium sulfate andconcentrated in vacuo to give a tan oil. Purification by flashchromatography eluting with hexanes/EtOAc (1:1) afforded the titlecompound as a yellowish solid (0.040 g). ¹H NMR (DMSO-d6, 400 MHz) δ9.70 (b, 1H), 9.19 (dd, 1H), 8.54-8.64 (m, 1H), 8.37 (s, 1H), 7.77(dd,1H), 7.64 (m, 2H), 7.32 (t, 1H), 6.87 (m, 1H); MS (m/e) calculated forC₁₆H₁₃ClN₂O 256, found 257.5 (M+H).

Example 5 7-(4′-Methoxybiphenyl-4-yl)-[1,6]naphthyridin-5-ol

To a suspension of 7-(4-bromophenyl)-[1,6]-naphthyridin-5-ol (0.135 g,0.45 mmol)) in DMF (4 mL), was addedtetrakis(triphenylphosphine)palladium (0.025 g, 0.02 mmol). After 15minutes, 4-methoxyphenylboronic acid (0.090 g, 0.60 mmol) and sodiumcarbonate (2 M aqueous solution, 0.5 mL, 1 mmol) was added. The mixturewas heated to 100° C. for 12 hours and then cooled to room temperature.The white solid was collected by filtration and washed with water toafford the title compound (0.110 g).

Example 65-(3-Aminopropylamino)-7-[6-dimethylamino-biphenyl-3-yl)-[1,6]naphthyridine

A mixture of 4-dimethylaminobenzonitrile (2.92 g, 20 mmol) andN-bromosuccinmide (3.56 g, 20 mmol) in dichloromethane (50 mL) wasstirred at room temperature overnight. The solution was washed withwater (20 mL), dried over magnesium sulfate and concentrated to afford3-bromo-4-dimethylaminobenzonitrile as a white solid (4.27 g).

Treatment of the above intermediate with 2-methylnicotinic acidaccording to Method A (Example 1) provided the corresponding[1,6]napthyridin-5-ol. Treatment of this with phenylboronic acid usingthe procedure described in Example 5 provided7-(6-dimethylamino-biphenyl-3-yl)-[1,6]naphthyridin-5-ol. Conversion tothe 5-chloro intermediate using Method B, followed by treatment of thiswith 1,3-diaminopropane by the procedure described in Method C (Example3) provided the title compound. ¹H NMR (CDCl₃, 400 MHz) δ 8.82 (dd, 1H),8.16 (d, 1H), 8.04 (dd, 1H), 8.00 (d, 1H), 7.63 (dd, 2H), 7.52 (s, 1H),7.41 (t, 2H), 7.29 (t, 1H), 7.19 (dd, 1H), 7.08 (d, 1H), 3.84 (t, 2H),3.00 (t, 2H), 2.58 (s, 6H), 1.99 (t, 2H); MS (m/e) calculated forC₂₅H₂₇N₅ 397, found 398.3 (M+H).

Example 75-(3-Aminopropylamino)-7-(3-chloro-4-diethylaminophenyl)-[1,6]naphthyridine

A sealed tube with 3-chloro-4-fluorobenzonitrile (0.366 g, 2.4 mmol) anddiethylamine (0.6 mL, 5.8 mmol) was heated to 100° C. for 8 hours. Thereaction was allowed to cool to room temperature and water (5 mL) wasadded. The solution was extracted with dichloromethane (2×5 mL), driedover magnesium sulfate and concentrated in vacuo to afford3-chloro-4-diethylaminobenzonitrile as an oil (0.38 g). This was reactedas described in Methods A-C (Examples 1-3) to provide the titlecompound. ¹H NMR (CDCl₃, 400 MHz) δ 8.89 (dd, 1H), 8.26 (d, 1H), 8.11(ddd, 1H), 7.97 (dd, 2.2 Hz, 1H), 7.53 (d, 1H), 7.27 (dd, 1H), 7.15 (d,1H), 3.86 (b, 2H), 3.20 (q, 4H), 3.03 (t, 2H), 1.91 (quint, 2H), 1.08(t, 6H); MS (m/e) calculated for C₂₁H₂₆ClN₅ 383, found 384.3 (M+H).

Example 85-(3-Aminopropylamino)-7-(3-methoxy-4-dimethylaminophenyl)-[1,6]naphthyridine

To a solution of 3-methoxy-4-aminobenzoic acid (1.5 g, 9 mmol) in DMF(10 mL) was added sodium hydride (60% in mineral oil, 1.5 g, 37.5 mmol)at 0° C. in portions. After stirring for 30 minutes, methyl iodide (6 g,45 mmol) was added. The mixture was stirred overnight and quenched byaddition of water. The aqueous mixture was extracted withdichloromethane (2×20 mL), dried over sodium sulfate and concentrated invacuo. Purification by flash chromatography eluting with hexane/EtOAc(4:1) afforded 3-methoxy-4-dimethylaminobenzoic acid as an oil (1.8 g).

A suspension of the above intermediate (1.20 g, 5.7 mmol) and sodiumamide (1.0 g, 25 mmol) in toluene (20 mL) was heated to 108° C. for 16hours. The solution was allowed to cool to room temperature, water wasadded dropwise, and the resulting mixture was extracted with EtOAc (2×20mL). The combined organic extracts were dried over sodium sulfate andconcentrated in vacuo. Purification by flash chromatography eluting withhexane and EtOAc (1:1) afforded 3-methoxy-4-dimethylaminobenzamide as anoil (0.35 g).

A mixture of the above benzamide (0.220 g, 1.25 mmol), POCl₃ (1 mL) anddiisopropylethylamine (0.5 mL) was heated to 105° C. for 16 hours andthen cooled to room temperature. The solution was poured into ice waterand neutralized with sodium carbonate, then extracted with EtOAc (2×20mL). The combined organic extracts were dried over sodium sulfate andconcentrated in vacuo. Purification by flash chromatography eluting withhexanes/EtOAc (2:1) afforded 3-methoxy-4-dimethylaminobenzonitrile as anoil (0.20 g).

The above benzonitrile was reacted as described in Methods A-C (Examples1-3) to provide the title compound. ¹H NMR (CD₃OD) δ 8.88 (b, 1H), 8.13(d, 1H), 7.74-7.77 (m, 2H), 7.56 (s, 1H), 7.21 (dd, 1H), 7.08 (b, 1H),7.02 (d, 1H), 4.00 (s, 3H), 3.88 (b, 2H), 2.85 (s, 6H), 1.96 (b, 2H); MS(m/e) calculated for C₂₀H₂₅N₅O 351, found 352 (M+H).

Example 95-(3-Aminopropylamino)-7-(4-diethylaminophenyl)-3-methyl-[1,6]naphthyridine

To a solution of N,N-diethyl-2,5-dichloronicotinamide (0.984 g, 4.0mmol) in THF (15 mL) was added palladium acetate (12 mg, 0.05 mmol) and2-(di-t-butylphosphino)biphenyl (28 mg, 0.09 mmol). After the mixturewas stirred for 5 minutes, methylzinc chloride (2 M solution indichloromethane, 4.5 mL, 9 mmol) was added. The contents were stirred atroom temperature for 14 hours. Water was added and THF was removed invacuo. The solution was extracted with EtOAc (2×20 mL) and the combinedorganic extracts were dried over sodium sulfate and concentrated invacuo. Purification by flash chromatography eluting with hexanes/EtOAc(1:1) afforded N,N-diethyl-2,5-dimethylnicotinamide as an oil (0.31 g).

The above diethylamide was reacted with 4-diethylaminobenzonitrile underconditions described in Method A (Example 1) and the resultingintermediate reacted as described in Methods B and C (Examples 2 and 3)to provide the title compound. ¹H NMR (CDCl₃, 400 MHz) δ 8.85 (d, 1H),7.29 (d, 1H), 3.65 (b, 2H), 3.13 (q, 2H), 2.47 (s, 3H), 2.31 (s, 3H),1.27 (t, 3H), 1.05 (t, 3H); MS (m/e) calculated for C₁₂H₁₈N₂O 206, found207 (M+H).

Example 105-(3-Aminopropylamino-7-(3′-fluorobiphenyl-3-yl)-[1,6]-naphthyridine

This example is representative of a procedure using a Suzuki reactioncarried out on a resin-bound intermediate. This procedure may be used toprepare compounds with a substituted biphenyl in the 7-position.

A suspension of5-(3-aminopropylamino)-7-(3-bromophenyl)-6H-[1,6]naphthyridine (250 mg,0.69 mmol) and p-nitrophenylcarbamate Wang resin (500 mg, 0.93 mmol/gloading, 0.47 mmol) in DMF (5 mL) was stirred overnight at roomtemperature. The suspension was filtered and the resin was washedsuccessively three times with DMF, MeOH, and dichloromethane, then driedunder vacuum overnight to afford resin bound compound.

The resin-bound compound above (50 mg, 0.0465 mmol),dichloro(bis-triphenylphosphine) palladium (3 mg, 0.0042 mmol),potassium carbonate (50 μl of a 400 mg/mL solution in water) and3-fluorophenylboronic acid (64 mg, 0.232 mmol) were suspended in a 7:3:2mixture of dimethoxyethane/water/EtOH and allowed to heat to 140° C. for30 minutes in a Smith Synthesizer microwave apparatus from PersonalChemistry. The reaction was filtered and washed three times successivelywith DMF, MeOH, and dichloromethane. The resin was then dried overnightunder vacuum and product was cleaved from the resin using 50%trifluoroacetic acid/dichloromethane (1 mL). The resin was filtered,washed once with 50% trifluoroacetic acid/dichloromethane (1 mL), andthe filtrate concentrated to dryness in vacuo to afford the titlecompound as a film (8 mg). MS (m/e) calculated for C₂₃H₂₁FN₄ 372.17,found 373.2 (M+H).

Example 115-(4-Aminobutoxy)-7-(4-dimethylaminophenyl)-[1,6]naphthyridine (MethodD)

This example is illustrative of a procedure that may be used to preparecompounds with a substituted alkoxy in the 5-position.

To a solution of 4-amino-1-butanol (100 μL, 1 mmol) in DMF (500 μL) wasadded sodium hydride (60% suspension in oil, 5 mg, 0.1 mmol), and thecontents stirred at room temperature for 20 minutes.5-Chloro-7-(4-dimethylaminophenyl)-[1,6]naphthyridine (Example 2) (15mg, 50 μmol) was added, and the contents stirred at room temperature for2 hours. Water (200 μL) was added to quench the reaction. Purificationby preparative TLC plate developed using 10% 2 M ammonia-MeOH indichloromethane afforded the title compound as a yellow solid (3 mg). MScalculated for C₂₀H₂₄N₄O 336, found (M+H) 337 (100%).

Example 12 7-(4-Dimethylaminophenyl)-8-iodo-[1,6]naphthyridin-5-ol

The following example illustrates how an iodo substituent may beintroduced in the 8-position. Further synthetic modification of the iodogroup by methods known to those skilled in the art may be carried out toobtain other desired substituents in the 8-position (see for instance,Example 13).

A solution of 7-(4-dimethylaminophenyl)-[1,6]naphthyridin-5-ol (Example1)

(293 mg, 1.10 mmol) and N-iodosuccinimide (261 mg, 1.16 mmol) in DMF (7mL) was stirred in the dark at room temperature for 4 hours. Thesolution was poured into dichloromethane (50 mL), washed with aqueoussodium bicarbonate (2×20 mL), dried over anhydrous magnesium sulfate andconcentrated in vacuo to afford the title compound as a yellow solid(390 mg). ¹H NMR (CD₃OD, 400 MHz) δ 8.95 (dd, 1H), 8.60 (dd, 1H), 7.53(dd, 1H), 7.40 (d, 2H), 6.84 (d, 2H), 2.86 (s, 6H).

Example 13 8-Cyano-7-(4-dimethylaminophenyl)-[1,6]naphthyridin-5-ol

A solution of 7-(4-dimethylaminophenyl)-8-iodo-[1,6]naphthyridin-5-ol(Example 12) (134 mg, 0.34 mmol), cuprous cyanide (123 mg, 1.37 mmol),tris(dibenzylideneacetone)dipalladium (13 mg, 0.0136 mmol) and1,1′-bis(diphenylphosphino)-ferrocene (30 mg, 0.054 mmol) in 1,4-dioxane(4 mL) was heated to 100° C. for 16 hours. The dark solution was allowedto cool to room temperature and EtOAc (10 mL) was added. This solutionwas poured through an extraction tube filled with diatomaceous earthloaded with saturated sodium bicarbonate solution, and a further 20 mLEtOAc was added to wash the tube. The combined organic extracts wereconcentrated in vacuo. Purification by flash chromatography eluting with2.5% MeOH/dichloromethane afforded the title compound as a yellow solid(24 mg). ¹H NMR (DMSO-d6, 400 MHz) δ 9.01 (dd, 1H), 8.52 (m, 1H), 7.64(d, 2H), 7.59 (dd, 1H), 6.85 (d, 2H), 3.03 (s, 6H), MS (m/e) calculatedfor C17H14N4O 290, found (M+H) 291 (100%).

The cyano group may be modified by methods known in the art to obtainadditional substituents in the 8-position. Intermediates may beconverted to compounds of formula (I) by Methods B and C.

Example 14 7-(4-Methoxyphenyl)-[1,6]naphthyridin-5-ol (Method E)

1-(4-Methoxyphenyl)acetylacetone (81 g, 0.5 mol) was added to a solutionof NaOEt in EtOH (18.7 g Na in 400 mL abs. EtOH) at room temperature.Then 2-chloronicotinic acid (53.5 g) and CuOAc (2.7 g) in 100 mL of EtOHwas added and the reaction was refluxed for 4 hours. The cooled solutionwas acidified with HOAc (330 mL). The material was purified by pouringinto CHCl₃/MeOH, filtering and evaporating. The resultant solid was thenwashed with benzene to give 61.7 g (67%)2-[2-(4-methoxyphenyl)-2-oxo-ethyl]-nicotinic acid, mp 158-163° C.

The above nicotinic acid derivative (20 g) was combined with dioxane(100 mL) and conc. NH₃ (200 mL) and heated to reflux. The product waswashed with H₂O and yielded 13.2 g (71%) of the title compound as abeige solid, mp 295-298° C.

Example 15 5-Chloro-7-(4-methoxyphenyl)-[1,6]naphthyridine (Method B)

7-(4-Methoxyphenyl)-[1,6]naphthyridin-5-ol (13 g) and POCl₃ (275 mL) washeated to 135° C. for 26 hours in a sealed tube. The mixture was cooledand the POCl₃ was evaporated. The residue was poured onto ice andneutralized with 2M Na₂CO₃ and the precipitate was filtered and washedwith H₂O to yield 13.8 g of the title compound (98.5%), mp 126-127° C.

Example 16 5-(3-Aminoethylamino)-7-(4-methoxyphenyl)-[1,6]naphthyridine

5-Chloro-7-(4-methoxyphenyl)-[1,6]naphthyridine (50 mg) was dissolved inethylenediamine (1 mL) and heated to 140° C. for 16 hours. The mixturewas concentrated and azeotroped with n-BuOH. The residue was treatedwith 1N NaOH (10 mL) and extracted with dichloromethane (2×50 mL). Theproduct was purified by column chromatography (dichloromethane/MeOH 0 to10%) to yield the title compound (20 mg, 92%), mp 134-136° C.

Example 17 7-(4-Methoxyphenyl)-[1,6]naphthyridin-5-yl]-methyl-amine(Method C)

5-Chloro-7-(4-methoxyphenyl)-[1,6]naphthyridine (75 mg) was suspended inaqueous methylamine (0.8 mL) and heated to 150° C. for 18 hours. Themixture was concentrated and azeotroped with EtOH (2×25 mL). The residuewas purified by column chromatography (dichloromethane/5% MeOH) andfinally recrystallized from ether to yield the title compound (39 mg,53%), mp 183-185° C.

Example 18 7-Phenyl-8-cyano-6H-[1,6]naphthyridin-5-one (Method E)

NaH (36 mg 1.5 mmol) was added in portions to anhydrous EtOH (4 mL)under N₂. After 30 minutes, benzoylacetonitrile (218 mg, 1. 5 mmol) wasadded, and the reaction mixture was allowed to stir under a nitrogenatmosphere for 30 minutes. 2-Chloronicotinamide (236 mg, 1.5 mmol) andCuOAc (36 mg, 0.3 mmol) were then added and the reaction mixture washeated to 50° C. The temperature was maintained for 10 days, after whichtime the reaction mixture was allowed to cool, was diluted with a 10%aqueous solution of NH₄Cl (25 mL), and extracted with three portions ofEtOAc (30 mL). The combined extracts were washed with brine, dried andevaporated to an oil which was triturated with CH₂Cl₂. The resultingsolid (39 mg) was recrystallized from EtOH providing 30 mg (7.3%) of thetitle compound, mp 292-5° C.

Example 19 7-(4-Methoxyphenyl)-2-trifluoromethyl-[1,6]naphthyridin-5-ol(Method A)

A solution of LDA (2.4 mmol) was prepared by adding n-BuLi (1.7 mL, 2.4mmol, 1.4 M in hexanes) via syringe to a solution of diisopropylamine(247 mg, 2.4 mmol) in THF (10 mL) at 0° C. and stirring for 15 minutes.The solution was then cooled to −40° C., then2-methyl-6-trifluoromethylnicotinic acid (250 mg, 1.2 mmol) in THF (5mL) was added via syringe. After stirring at −40° C. for 30 minutes,4-methoxybenzonitrile (162 mg, 1.2 mmol) in THF (5 mL) was added viasyringe. The reaction mixture was allowed to warm to room temperatureand stirred for 16 hours. The reaction was quenched by addition of sat.NH₄Cl solution. A precipitate formed which was collected by vacuumfiltration giving the title compond (150 mg, 40%) as an off white solid.

Example 205-Chloro-7-(4-methoxyphenyl)-2-trifluoromethyl-[1,6]naphthyridine(Method B)

POCl₃ (3 mL) was added to7-(4-methoxyphenyl)-2-trifluoromethyl-[1,6]naphthyridin-5-ol (Example19) (125 mg, 0.4 mmol). The mixture was heated at 100° C. for 3 hours.The excess POCl₃ was concentrated under reduced pressure. The residuewas diluted with CH₂Cl₂, washed with sat. NaHCO₃, dried over Na₂SO₄, andconcentrated giving the title compound (73 mg, 55%) as an orange solid.

Example 215-(3-Aminopropylamino)-2-trifluoromethyl-7-(4-methoxyphenyl)-[1,6]naphthyridine(Method C)

A mixture of5-chloro-7-(4-methoxy-phenyl)-2-trifluoromethyl-[1,6]naphthyridine (55mg, 0.2 mmol) and 1,3-diaminopropane (2.5 mL) in a sealed reactionvessel was heated at 100° C. for 3 hours. The mixture was diluted withtoluene and concentrated three times to azeotropically remove excess1,3-diaminopropane. The residue was diluted with EtOAc, washedsequentially with sat. NaHCO₃, H₂O, sat. NaCl, dried over Na₂SO₄, andconcentrated giving the title compound (60 mg, quantitative) as a yellowsolid.

Example 22 7-(4-Methoxyphenyl)-3-bromo-[1,6]naphthyridin-5-ol (Method E)

A solution of NaOEt (0.6 mmol) was prepared by adding Na (15 mg, 0.6mmol) to EtOH (5 mL) and stirring at room temperature for 30 minutes.1-(4-Methoxyphenyl)-butane-1,3-dione (121 mg, 0.6 mmol) was added andthe mixture was stirred at room temperature for 15 minutes. Then5-bromo-2-chloronicotinic acid (100 mg, 0.4 mmol) and CuOAc (10 mg,catalytic) was added. The mixture was then heated to reflux for 4 hours.The mixture was cooled to room temperature and quenched by addition ofHOAc (0.5 mL). The mixture was concentrated, then diluted with EtOAc andwashed with 1M NaOH (×2). The basic washings were acidified with 6N HCl(pH ˜3). A precipitate formed and was collected by vacuum filtrationgiving after air drying5-bromo-2-[2-(4-methoxyphenyl)-2-oxo-ethyl]-nicotinic acid (65 mg, 44%)as a light brown solid.

The above nicotinic acid derivative (310 mg, 0.5 mmol) in ethanolicammonia (2 mL, 0.2M) was heated at 90° C. in a sealed reaction vesselfor 20 hours. A precipitate formed upon cooling, and was collected byvacuum filtration giving the title compound (120 mg, 73%) as an offwhite solid.

Example 235-(3-Aminopropylamino)-3-bromo-7-(4-methoxyphenyl)-[1,6]naphthyridine(Methods B and C)

POCl₃ (3 mL) was added to7-(4-methoxyphenyl)-3-bromo-[1,6]naphthyridin-5-ol (Example 22) (115 mg,0.4 mmol). The mixture was heated at 100° C. for 3 hours. The excessPOCl₃ was concentrated under reduced pressure. The residue was dilutedwith CH₂Cl₂, washed with sat. NaHCO₃, dried over Na₂SO₄, andconcentrated giving5-chloro-7-(4-methoxyphenyl)-3-bromo-[1,6]naphthyridine (115 mg, 94%) asa yellow solid.

A mixture of the above intermediate (98 mg, 0.3 mmol) and1,3-diaminopropane (3 mL) in a sealed reaction vessel was heated at 100°C. for 3 hours. The mixture was diluted with toluene and concentratedthree times to azeotropically remove excess 1,3-diaminopropane. Theresidue was triturated with 25% MeOH/Et₂O giving the title compound (7mg, 7%) as an orange solid.

Example 245-(3-Aminopropylamino)-7-(4-methoxyphenyl)-3-phenyl-[1,6]naphthyridine

Argon gas was bubbled through a mixture of the product of Example 23 (68mg, 0.2 mmol), PhB(OH)₂ (33 mg, 0.3 mmol), and Pd(PPh₃)₄ (25 mg, 0.02mmol) in 2M Na₂CO₃ (1 mL)/EtOH (1 mL)/benzene (3 mL) for 10 minutes. Themixture was then heated to reflux for 20 hours. After cooling to roomtemperature the mixture was partitioned between EtOAc and H₂O. Theorganic material was washed with sat. NaCl, dried over Na₂SO₄, andconcentrated. The crude residue was fractionated by columnchromatography on silica gel (50% EtOAc/45% EtOH/5% NH₄OH) giving thetitle compound (10 mg, 15%) as a light yellow solid.

Example 25 2-Chloro-7-(4-methoxy-phenyl)-[1,6]naphthyridin-5-1 (MethodF)

Elemental sodium (173 mg, 7.5 mmol) was added to 40 mL of absolute EtOHstirring under nitrogen. After all of the sodium reacted,4-methoxyacetophenone (1.44 g, 7.5 mmol) was added, and the reactionstirred an additional 15 minutes . 2,6-Dichloronicotinic acid (1 g, 5.2mmol) and copper acetate (80 mg, 0.65 mmol) was added and the reactionwas stirred at reflux for 16 hours. The reaction was cooled to roomtemperature and quenched with 1 mL concentrated acetic acid. The mixturewas concentrated to a solid, and redissolved in EtOAc. A small portionof fine inorganic precipitate was filtered off. The organic layer wasextracted with 3×100 mL 1N NaOH. This was acidified with 1 N HCl to a pHof ˜4. A precipitate formed and was collected by vacuum filtration,yielding 6-chloro-2-[2-(4-methoxyphenyl)-2-oxo-ethyl]-nicotinic acid (1g, 63%) as a tan solid.

The above nicotinic acid derivative (1 g, 3.27 mmol) was dissolved in50% aqueous sulfuric acid v/v (10 mL) and stirred at room temperaturefor 20 hours. The reaction started as a yellow solution, and aprecipitate formed after an hour. The reaction was added to ice waterand a fine yellow precipitate formed. This was collected by vacuumfiltration, yielding2-chloro-7-(4-methoxyphenyl)-pyrano[4,3-b]pyridin-5-one (876 mg, 93%) asa light yellow solid.

The above intermediate (225 mg, 0.78 mmol) and 2M ammonia in EtOH (15mL) were combined and heated to 80° C. for 16 hours. A heavy whiteprecipitate formed. Vacuum filtration yielded the title compound (164mg, 73%) as a white solid.

Example 262,5-Bis-(Aminopropylamino)-7-(4-methoxyphenyl)-[1,6]naphthyridine

2-Chloro-7-(4-methoxyphenyl)-[1,6]naphthyridin-5-ol (135 mg, 0.47 mmol)was dissolved in phosphorus oxychloride (2 mL, 21.5 mmol) and refluxedfor 3 hours. An orange solid precipitated. The reaction mixture wasdiluted with dichloromethane (25 mL) and concentrated to an orangesolid. The solid was re-dissolved in EtOAc (300mL) and washed withsaturated sodium bicarbonate solution (100 mL), brine (100 mL) and driedover magnesium sulfate. Filtration and concentration yielded2,5-dichloro-7-(4-methoxy-phenyl)-[1,6]naphthyridine (138 mg, 86%) as ayellow solid.

The above intermediate (135 mg, 0.44 mmol), (3-aminopropyl)-carbamicacid tert-butyl ester (0.31 mL, 1.77 mmol), and diethyl propylamine(0.15 mL, 0.88 mmol) were combined in methoxyethanol (5 mL) and stirredat 120° C. for 16 hours. Column chromatography afforded{3-[5-chloro-7-(4-methoxyphenyl)-[1,6]naphthyridin-2-ylamino]-propyl}-carbamicacid tert-butyl ester (148 mg, 76%).

A mixture of the above intermediate (50 mg, 0.113 mmol) and1,3-diaminopropane (1 mL, 12 mmol) in a sealed reaction vessel washeated at 115° C. for 3 hours. The mixture was diluted with toluene andconcentrated three times to azeotropically remove excess1,3-diaminopropane. The residue was triturated to a solid with ether andfiltered. The product was purified on a preparatory TLC plate, providing{3-[5-(3-aminopropylamino)-7-(4-methoxyphenyl)-[1,6]naphthyridin-2-ylamino]-propyl}-carbamicacid tert-butyl ester (53 mg, 99%).

The above carbamic acid tert-butyl ester (50 mg, 0.104 mmol) was stirredin 4N HCl in dioxane (2 mL) for 4 hours. A fine precipitate formed whichwas filtered and re-dissolved in slightly acidic MeOH. Solid phaseextraction on a Varian SCX cartridge (2 g) afforded the title compound(4 mg, 8%).

Example 275-(3-Aminopropylamino)-2-benzyloxy-7-(4-methoxyphenyl)-[1,6]naphthyridine

2,5-Dichloro-7-(4-methoxyphenyl)-[1,6]naphthyridine (Example 26) (700mg, 2.29 mmol) was stirred in saturated sodium bicarbonate solution (100mL) for 20 minutes. A white solid precipitated and was isolated byvacuum filtration to afford5-chloro-7-(4-methoxy-phenyl)-1H-[1,6]naphthyridin-2-one (209 mg, 32%).

The above intermediate (100 mg, 0.35 mmol), benzyl bromide (0.05 mL,0.42 mmol), and silver carbonate (115 mg, 0.42 mmol) were combined inTHF (5 mL) and stirred at room temperature for 72 hours. The reactionmixture was filtered to remove inorganic salts, and concentrated to anoil. Column chromatography afforded2-benzyloxy-5-chloro-7-(4-methoxyphenyl)-[1,6]naphthyridine (61 mg,46%).

A mixture of the above intermediate (61 mg, 0.162 mmol),1,3-diaminopropane (2 mL, 24 mmol), and methoxyethanol (2 mL) in asealed reaction vessel was heated at 120° C. for 24 hours. The mixturewas diluted with toluene and concentrated three times to azeotropicallyremove excess 1,3-diaminopropane. Column chromatography yielded thetitle compound (45 mg, 67%).

Example 285-(3-Aminopropylamino)-2-benzylamino-7-(4-methoxyphenyl)-[1,6]naphthyridine

2,5-Dichloro-7-(4-methoxyphenyl)-[1,6]naphthyridine (147 mg, 0.48 mmol)and benzyl amine (0.055 mL, 0.5 mmol) were combined in methoxyethanol (2mL) and stirred at 80° C. for 72 hours. The crude reaction mixture wasconcentrated, and column chromatography affordedbenzyl-[5-chloro-7-(4-methoxyphenyl)-[1,6]naphthyridin-2-yl]-amine (55mg, 30%).

A mixture of the above intermediate (50 mg, 0.133 mmol),1,3-diaminopropane (2 mL, 24 mmol), and methoxyethanol (2 mL) in asealed reaction vessel was heated at 120° C. for 24 hours. The mixturewas diluted with toluene and concentrated three times to azeotropicallyremove excess 1,3-diaminopropane. Preparatory TLC afforded the titlecompound (46 mg, 83%).

Assessment of Biological Properties

The inhibition of SYK kinase was measured with the following assay.

SYK was purified as a GST-fusion protein. The kinase activity wasmeasured using DELFIA (Dissociation Enhanced LanthanideFluoroimmunoassay) which utilizes europium chelate-labeledanti-phosphotyrosine antibodies to detect phosphate transfer to a randompolymer, poly Glu₄:Tyr₁ (PGTYR).

The kinase assay was performed in kinase assay buffer (50 mM HEPES, pH7.0, 25 mM MgCl₂, 5 mM MnCl₂, 50 mM KCl, 100 μM Na₃VO₄, 0.2% BSA, 0.01%CHAPS). Test samples initially dissolved in DMSO at 1 mg/mL, werepre-diluted for dose response (11 doses with starting finalconcentration of 30 μg/mL, 1 to 3.5 serial dilutions) with the assaybuffer in 96-well polypropylene microtiter plates. A 25 μL aliquot ofthis diluted sample was added to neutravidin coated 96-well white plate(PIERCE). A 25 μL volume of diluted enzyme (0.6 ng/mL final conc.) and a50 μL volume of a mixture of substrates containing 200 nM ATP and 3.6ng/μL PGTYR-biotin (CIS Biointernational) in kinase buffer wassequentially added to the assay plates. Background wells were incubatedwith buffer, rather than 25 μL enzyme. The assay plates were incubatedfor 30 minutes at room temperature. Following incubation, the assayplates were washed three times with 300 μL wash buffer (50 mM Tris-HCL,pH 7.4, 150 mM NaCl, 0.05% Tween 20, 0.2% BSA). A 100 μL aliquot ofeuropium-labeled anti-phosphotyrosine (Eu³⁺-PT66, Wallac CR04-100)diluted in 50 mM Tris-HCl, pH 7.8, 150 mM NaCl, 10 μM DTPA, 0.05% Tween40, 0.2% BSA, 0.05% BGG (1 nM final conc.) was added to each well andincubated for 30 minutes at room temperature. Upon completion of theincubation, the plate was washed four times with 300 μL of wash bufferand 100 μL of DELFIA Enhancement Solution (Wallac) was added to eachwell. After 10 minutes or longer, time-resolved fluorescence wasmeasured on the LJL's Analyst (excitation at 360 nm, emission at 620 nm,EU 400 Dichroic Mirror) after a delay time of 250 μs.

Compounds of the invention including those in the Synthetic Examplessection and those listed individually in the Detailed Description of theInvention section were evaluated for inhibition of SYK kinase in thisassay. All had IC₅₀s below 30 μM, preferred compounds had IC₅₀s below 1μM.

Methods of Therapeutic Use

The compounds of the invention are useful in inhibiting the activity ofSYK kinase. In doing so, these compounds are useful in blocking diseaseprocesses mediated by SYK kinase. Compounds of the invention effectivelyblock activation of mast cells by inhibiting SYK kinase. This in turnprevents the release of inflammatory mediators including histamine,proteases, leukotrienes and cytokines. These mediators play a key rolein the etiology of allergic and inflammatory disorders. Preventing therelease of these mediators is a desirable means for treating theseconditions. Thus there are provided methods for treating theseconditions using the compounds of the invention. These includeinflammatory and allergic conditions involving mast cell activation,including but not limited to asthma, chronic obstructive pulmonarydisease (COPD), adult respiratory distress syndrome (ARDS), ulcerativecolitis, Crohn's disease bronchitis, conjunctivitis, psoriasis,scleroderma, urticaria, dermatitis and allergic rhinitis. They alsoinclude inflammatory conditions where B cells contribute to the etiologyof the disease, including but not limited to lupus and rheumatoidarthritis. The compounds of the invention can also be used to treatother disorders associated with inappropriate mast cell or B cellactivation, unrelated to those listed above or discussed in theBackground of the Invention. Therefore, the invention also providesmethods of treating allergic and inflammatory diseases comprisingadministering to a patient in need of such treatment a pharmaceuticallyeffect amount of a compound according to the invention.

For therapeutic use, the compounds of the invention may be administeredin any conventional dosage form in any conventional manner. Routes ofadministration include, but are not limited to, intravenously,intramuscularly, subcutaneously, intrasynovially, by infusion,sublingually, transdermally, orally, topically or by inhalation. Thepreferred modes of administration are oral and intravenous. Compositionscomprising the compounds of the invention for each of the aforementionedroutes of administration will be apparent to the skilled artisan. Theinvention also provides for pharmaceutical compositions including atherapeutically effective amount of the compounds according to theinvention. Such pharmaceutical compositions will includepharmaceutically acceptable carriers and adjuvants as further describedbelow.

The compounds of this invention may be administered alone or incombination with adjuvants that enhance stability of the inhibitors,facilitate administration of pharmaceutical compositions containing themin certain embodiments, provide increased dissolution or dispersion,increase inhibitory activity, provide adjunct therapy, and the like,including other active ingredients. Advantageously, such combinationtherapies utilize lower dosages of the conventional therapeutics, thusavoiding possible toxicity and adverse side effects incurred when thoseagents are used as monotherapies. Compounds of the invention may bephysically combined with the conventional therapeutics or otheradjuvants into a single pharmaceutical composition. Advantageously, thecompounds may then be administered together in a single dosage form. Insome embodiments, the pharmaceutical compositions comprising suchcombinations of compounds contain at least about 15%, but morepreferably at least about 20%, of a compound of the invention (w/w) or acombination thereof. Alternatively, the compounds may be administeredseparately (either serially or in parallel). Separate dosing allows forgreater flexibility in the dosing regime.

As mentioned above, dosage forms of the compounds of this inventioninclude pharmaceutically acceptable carriers and adjuvants known tothose of ordinary skill in the art. These carriers and adjuvantsinclude, for example, ion exchangers, alumina, aluminum stearate,lecithin, serum proteins, buffer substances, water, salts orelectrolytes and cellulose-based substances. Preferred dosage formsinclude, tablet, capsule, caplet, liquid, solution, suspension,emulsion, lozenges, syrup, reconstitutable powder, granule, suppositoryand transdermal patch. Methods for preparing such dosage forms are known(see, for example, H. C. Ansel and N. G. Popovish, Pharmaceutical DosageForms and Drug Delivery Systems, 5th ed., Lea and Febiger (1990)).Dosage levels and requirements are well-recognized in the art and may beselected by those of ordinary skill in the art from available methodsand techniques suitable for a particular patient. In some embodiments,dosage levels range from about 10-1000 mg/dose for a 70 kg patient.Although one dose per day may be sufficient, up to 5 doses per day maybe given. For oral doses, up to 2000 mg/day may be required. As theskilled artisan will appreciate, lower or higher doses may be requireddepending on particular factors. For instance, specific dosage andtreatment regimens will depend on factors such as the patient's generalhealth profile, the severity and course of the patient's disorder ordisposition thereto, and the judgment of the treating physician.

1. A method of making a compound of formula (I) below:

wherein R₃ is H, C₁₋₃alkyl, halogen or phenyl; R₅ is N(R₉)(R₁₀) whereinR₉ is H or C₁₋₃alkyl; R₁₀ is aminoC₂₋₆alkyl, C₁₋₄alkylaminoC₂₋₆alkyl,diC₁₋₄alkylaminoC₂₋₆alkyl, C₁₋₄alkoxyC₂₋₆alkyl or hydroxyC₂₋₆alkyl,wherein one methylene group in said C₂₋₆alkyl is optionally replacedwith an oxygen, sulfur, NH, or NCH₃, and wherein each methylene group insaid C₂₋₆alkyl is optionally substituted with a halogen, cyano orhydroxy group, or R₁₀ is C₃₋₇cycloalkyl, heterocycloalkyl, heteroaryl,C₃₋₇cycloalkylC₁₋₄alkyl, heterocycloalkylC₁₋₄alkyl, arylC₁₋₄alkyl orheteroarylC₁₋₄alkyl each optionally substituted with one or moreC₁₋₄alkyl, amino, C₁₋₄alkylamino, diC₁₋₄alkylamino, aminoC₁₋₃alkyl,C₁₋₄alkylaminoC₁₋₃alkyl, diC₁₋₄alkylaminoC₁₋₃alkyl, halogen, hydroxy,aminocarboxy or benzyl groups, or R₉ and R₁₀ together with the nitrogenthey are bonded to may form a heterocycloalkyl group containing one ormore heteroatoms which is optionally substituted with one or moreC₁₋₄alkyl, amino, C₁₋₄alkylamino, diC₁₋₄alkylamino, aminoC₁₋₃alkyl,C₁₋₄alkylaminoC₁₋₃alkyl, diC₁₋₄alkylaminoC₁₋₃alkyl, halogen, hydroxy,aminocarboxy or benzyl groups; R₇ is phenyl, naphthyl, furyl, thienyl,pyridyl, indolyl, benzothiazolyl or pyrrolyl optionally substituted withone or more C₁₋₃alkoxy, halogen, CF₃, CF₃O, hydroxy, C₁₋₃alkyl, amino,C₁₋₃alkylamino, diC₁₋₃alkylamino, C₁₋₃alkylaminoC₁₋₃alkyl,diC₁₋₃alkylaminoC₁₋₃alkyl, (C₁₋₃alkylaminoC₁₋₃alkyl)(C₀₋₃alkyl)amino,(diC₁₋₃alkylaminoC₁₋₃alkyl)(C₀₋₃alkyl)amino, C₁₋₃alkylthio,aminocarboxy, C₁₋₃alkylcarbonyl, ureido optionally substituted withC₁₋₃alkyl, C(O)OC₁₋₄alkyl, C(O)OH, acetamido or heterocycloaklyl groups,or with a phenyl group which is optionally substituted with one or moreC₁₋₃alkoxy, halogen, CF₃, CF₃O, hydroxy, C₁₋₃alkyl, amino,C₁₋₃alkylamino, diC₁₋₃alkylamino, C₁₋₃alkylaminoC₁₋₃alkyl,diC₁₋₃alkylaminoC₁₋₃alkyl, C₁₋₃alkylthio, aminocarboxy,C₁₋₃alkylcarbonyl, ureido optionally substituted with C₁₋₃alkyl,C(O)OC₁₋₄alkyl, C(O)OH, acetamido, heteroaryl or heterocycloalkylgroups; and R₈ is H; with the proviso that R₃ is not hydrogen when R₇ ismethoxy-subsituted phenyl and R₅ is

said method comprising: (a) reacting the compound of formula (II) with anitrile of the formula R₇CN in the presence of a strong base in asuitable solvent to form a compound of formula (III):

(b) reacting the compound of formula (III) with a suitable chlorinatingagent to form the compound of formula (IV):

(c) reacting the compound of formula (IV) with an amine of the formulaHN(R₈)(R₉) to provide the desired compound of formula (I) wherein R₅ isN(R₈)(R₉) and R₈ is H:


2. A method of making a compound of formula (I) below:

wherein R₃ is H, C₁₋₃alkyl, halogen or phenyl; R₅ is OR₁₁ wherein R₁₁ isaminoC₂₋₆alkyl, C₁₋₄alkylaminoC₂₋₆alkyl, diC₁₋₄alkylaminoC₂₋₆alkyl,C₁₋₄alkoxyC₂₋₆alkyl or hydroxyC₂₋₆alkyl, wherein one methylene group insaid C₂₋₆alkyl is optionally replaced with an oxygen, sulfur, NH, orNCH₃, and wherein each methylene group in said C₂₋₆alkyl is optionallysubstituted with a halogen, cyano or hydroxy group, or R₁₁ isC₃₋₇cycloalkyl, heterocycloalkyl, heteroaryl, C₃₋₇cycloalkylC₁₋₄alkyl,heterocycloalkylC₁₋₄alkyl, arylC₁₋₄alkyl or heteroarylC₁₋₄alkyl eachoptionally substituted with one or more C₁₋₄alkyl, amino,C₁₋₄alkylamino, diC₁₋₄alkylamino, aminoC₁₋₃alkyl,C₁₋₄alkylaminoC₁₋₃alkyl, diC₁₋₄alkylaminoC₁₋₃alkyl, halogen, hydroxy,aminocarboxy or benzyl groups; R₇ is phenyl, naphthyl, furyl, thienyl,pyridyl, indolyl, benzothiazolyl or pyrrolyl optionally substituted withone or more C₁₋₃alkoxy, halogen, CF₃, CF₃O, hydroxy, C₁₋₃alkyl, amino,C₁₋₃alkylamino, diC₁₋₃alkylamino, C₁₋₃alkylaminoC₁₋₃alkyl,diC₁₋₃alkylaminoC₁₋₃alkyl, (C₁₋₃alkylaminoC₁₋₃alkyl)(C₀₋₃alkyl)amino,(diC₁₋₃alkylaminoC₁₋₃alkyl)(C₀₋₃alkyl)amino, C₁₋₃alkylthio,aminocarboxy, C₁₋₃alkylcarbonyl, ureido optionally substituted withC₁₋₃alkyl, C(O)OC₁₋₄alkyl, C(O)OH, acetamido or heterocycloaklyl groups,or with a phenyl group which is optionally substituted with one or moreC₁₋₃alkoxy, halogen, CF₃, CF₃O, hydroxy, C₁₋₃alkyl, amino,C₁₋₃alkylamino, diC₁₋₃alkylamino, C₁₋₃alkylaminoC₁₋₃alkyl,diC₁₋₃alkylaminoC₁₋₃alkyl, C₁₋₃alkylthio, aminocarboxy,C₁₋₃alkylcarbonyl, ureido optionally substituted with C₁₋₃alkyl,C(O)OC₁₋₄alkyl, C(O)OH, acetamido, heteroaryl or heterocycloalkylgroups; and R₈ is H; with the proviso that R₃ is not hydrogen when R₇ ismethoxy-subsituted phenyl and R₅ is

said method comprising: (a) reacting the compound of formula (II) with anitrile of the formula R₇CN in the presence of a strong base in asuitable solvent to form a compound of formula (III):

(b) reacting the compound of formula (III) with a suitable chlorinatingagent to form the compound of formula (IV):

(c) reacting the compound of formula (IV) with an alcohol of the formulaHO(R₁₀) in the presence of a suitable base in a suitable solvent toprovide the desired compound of formula (I) wherein R₅ is OR₁₀ and R₈ isH: